Critically injured patients are not a homogenous group, and the state of their inflammatory response is in flux, ranging from hyperactivation to immunosuppression. The cellular control switches that regulate these responses include an extensive network of intracellular signal transduction pathways, such as the mitogenactivatedprotein kinase (MAPK) families. We have focused on p38 and ERK, two important MAPK families, regulating inflammatory response and apoptosis. In order to elucidate the different pathways involved in MAPK activation we have devised an in vitro experimental model. Using peritoneal macrophages from wild type, CD14 knockout, and lipopolysaccharide-binding-protein (LBP) knockout mice, we will examine different pathways of cell and MAPK activation in response to lipopolysaccharide (LPS) stimulation. Surprisingly, our preliminary data demonstrated that LPS activates p38 MAPK in the CD14 knockouts as much or more than the wild type. This suggests a non-CD14 pathway for LPS-induced p38 MAPK activation. In a second set of experiments, we will investigate the potential therapeutic approaches by modifying MAPK activation. The United States ranks first among industrialized nations in death and disability from burn injuries. There is a progressive cell death and apoptosis that extends to several days after the initial thermal injury. In epithelial cells p38 activation is pro-apoptotic, while ERK activation inhibits apoptosis. We hypothesize that inhibiting p38 and/or activating ERK will inhibit cell death in response to thermal injury. The goal is to prevent conversion of a partial-thickness burn, which may heal primarily, to a full-thickness burn. In an in vivo thermal injury wound model, we will investigate the efficacy and safety of topical mitogen-activated protein kinase inhibitors/activators. We will first characterize the dermal MAPK activation, cytokine production, and epithelial apoptosis in response to burn injury in mice. We will then use topical inhibitors of both p38 and activators of ERK to study their effect on cell death. This grant proposal is composed of a training plan through the completion of core curriculum of courses and frequent didactic sessions with mentors and advisors. The candidate will gain knowledge of advanced techniques under the tutlelage of Dr. Stewart C. Wang, while working on the research proposal. The goal is for the candidate to become an independent researcher with his own grants.